The TNF (Tumor Necrosis Factor) and TNF receptor superfamilies (TNFSF and TNFRSF) consist of approximately 50 membrane and soluble proteins that can modulate cellular function. Most of these molecules are expressed by or can target cells of the immune system, and they have a wide range of actions including promoting cellular differentiation, survival, and production of inflammatory cytokines and chemokines. Members of the TNFRSF(Tumor Necrosis Factor Receptor superfamily) participate prominently in B-cell maturation and function. In particular, BAFFR (B-cell Activating Factor receptor) belonging to the TNF family receptor, BCMA (B-Cell Maturation Antigen), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) play critical roles in promoting B-cell survival at distinct stages of development by engaging a proliferation-inducing ligand APRIL (A Proliferation-Inducing Ligand) and/or BAFF (Ref.1).
APRIL, also known as TALL2 (TNF- and APOL-related Leukocyte expressed Ligand-2), has no essential function in normal B cell development and plays only a minor role in B cell homeostasis. In immune responses APRIL acts as a costimulator for B and T cell proliferation and supports class switch. In general, cytokines of the TNF superfamily are functional both in their membrane-bound and in soluble form when shed by enzymatic cleavage from the surface through a furin-like convertase. APRIL is secreted following intracellular processing in the Golgi apparatus. APRIL binds to two separate receptors, the TACI (Transmembrane Activator and Calcium modulator ligand Interactor), and the BCMA (B Cell Maturation Antigen). Both receptors are expressed on B cells, although their expression level changes with B cell maturation (Ref. 2). These receptors are functional as their ligation triggers activation of NF-KappaB, p38 MAPK/JNK, and AKT signaling. APRIL may also induce apoptosis through its interaction with other TNF receptor family proteins such as TNFRSF6/FAS and TNFRSF14/HVEM.
Signaling through TACI in mature B cells or plasmablasts are only achieved by higher-order APRIL oligomers, all of which were also potent activators of a multimerization-dependent reporter signaling pathway. Intracellular domain interacts with TNFR-associated factor TRAF2, 5, and 6. TRAFs are trimeric intermediates in the signaling pathway of numerous TNF receptor family members. By bringing together the receptors, a trimeric ligand may allow recruitment to the complex of just one intracellular TRAF, which may not be enough to induce signaling, as oligomerization of trimeric TRAF2 and TRAF6 is required to activate downstream signaling events (Ref. 3). Cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-KappaB signaling pathways via a Toll–interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-KappaB through a Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway (Ref. 4 and 5). BCMA binds to APRIL with high affinity. BCMA enhances B cell antigen presentation by recruiting TRAF proteins and activating NF-KappaB. BCMA might regulate post-CSR events, including the differentiation and survival of mucosal IgA-secreting plasma cells (Ref. 6).